Objective To investigate the association of genetic variants in PCSK1 gene, which encodes PC1/3, with the risk of Coronary Artery Disease (CAD) in the Chinese Han population with Type 2 Diabetes (T2DM). Methods From HapMap phase II (r2 < 0.8 and MAF ≥ 0.05, R#27) CHB database, 5 haplotype-tagging single nucleotide polymorphisms (SNPs), rs6230 (T > C), rs6233 (T > C), rs6234 (C > G), rs156019 (T > A) and rs3811951 (A > G), in PCSK1 were genotyped in 683 unrelated Chinese Han subjects with T2DM, of whom 425 individuals were CAD-positive cases and other 258 were CAD-negative controls. The associations between the 5 SNPs and risk of CAD were tested by chi-square test and multivariate logistic regression analysis adjusted for confounders. Results The allele frequencies at rs3811951 were significantly different in cases and controls (30.7% vs. 37.2%), with the allele G at a decreased risk for CAD (OR = 0.748, 95%CI = 0.59-0.94, P = 0.013). And in recessive inheritance mode, the carriers of GG had a lower risk (OR = 0.504, 95%CI = 0.31-0.82, P = 0.005), even after adjusted for the other known CAD risk factors (OR’ = 0.430, 95%CI’ = 0.24-0.77, P’ = 0.004, after adjustment for gender, age, BMI and smoking status). At rs156019, the carriers of minor allele A had a higher risk (OR = 1.575, 95%CI = 1.13-2.19, P = 0.007; OR’ = 1.659, 95%CI’ = 1.101-2.502, P’ = 0.016 after adjustment) in dominant inheritance mode. The SNP rs6234 was also associated with CAD risk, predominantly in women. Females carrying minor allele G at rs6234 had a reduced risk in recessive inheritance mode (OR’ = 0.416, 95%CI’ = 0.18-0.95, P’ = 0.036 after adjustment). Conclusion The genetic variants in PCSK1 are associated with CAD in the Chinese patients with T2DM.